Project Summary The parent grant CA10062 is focused on evaluation of function of myeloid-derived suppressor cells (MDSCs). During implementation of the research project we observed novel function of myeloid cells that are linked with the main focus of the grant but represent substantial extension of the proposed research. It is well established that the main causes of high mortality of lung cancer are frequent recurrence and metastasis. For patients with early stages non-small cell lung cancer (NSCLC) surgical resection is the treatment of choice. However, despite complete tumor resection followed by radiation control 30-60% of patients will undergo local or distant recurrence with limited benefit of adjuvant chemo- or targeted therapy. The reason for the recurrence remains unclear. It is widely accepted that small numbers of tumor cells persist in dormant state after early dissemination from primary tumor. Tumor microenvironment contribution to the development of lung cancer dormancy has been suggested. However, the mechanisms by which tumor cells are reawakened from dormancy remain poorly understood. This makes therapeutic targeting of this process is not possible. In this administrative supplement proposal, we will investigate the role of MDSC and activated neutrophils in re-activation of dormant tumor cells and evaluate a specific targeting strategy to block this effect. Three specific aims are proposed. Specific Aim 1. To identify the mechanism of PMN-mediated reactivation of dormant tumor cells in the models of genetic and chemotherapy-induced dormancy; Specific Aim 2. To determine therapeutic effect of targeting S100A9/A8 and ?2-adrenergic receptors on re-activation of dormant tumor cells. Specific Aim 3. To investigate the molecule mechanism underlying PMN-mediated escaping of senescence of dormant tumor cells This proposal is a collaborative effort of Dr. Gabrilovich, who has expertise in tumor immunology and cell biology and experience in studying neutrophils and MDSC, and Dr. Zhang who is molecular and cell biologist and an expert in studying of tumor cell senescence and dormancy.